Combined hamartoma of the retina and retinal pigment epithelium is a rare benign hamartoma made up of glial cells, vascular tissue, and pigment epithelial cells of the retina and retinal pigment epithelium. A hamartoma refers to a benign, localized overgrowth made of mature tissue that normally exists in that area but grows in a disorganized way.
In 1973, Gass first named this disease in a report of seven cases. Since then, several important reports have been published, including a systematic review of 60 cases by the Macula Society Study Group and a large series of 77 consecutive cases.
Epidemiologically, it is diagnosed mainly in childhood, with a median age at diagnosis of 7.5 years. The average tumor diameter has been reported as 7.6 mm and the thickness as 1.9 mm2). Almost all cases are unilateral and solitary. Findings on sex distribution vary across studies, ranging from reports of nearly equal numbers of men and women to a male predominance (70%, 68%). It is said to be more common in White patients.
This disease ranges from a simple hamartoma made up only of retinal pigment epithelium to a mixed hamartoma with glial cell proliferation, and it is generally considered a congenital, nonhereditary condition.
Combined hamartoma of the retina and retinal pigment epithelium is a benign hamartoma, and no cases of malignant transformation have been reported. However, it is important to make an accurate diagnosis because its clinical appearance can resemble choroidal melanoma and retinoblastoma.
By location, it occurs in 76% around the optic disc, 17% in the macula, and 7% in the periphery4). The tumor is dark brown, green, yellow, gray, or orange, and is raised with pigmentation.
The differences in visual acuity at first visit by tumor location are marked.
| Site | Average visual acuity | Proportion with 20/200 or worse |
|---|---|---|
| Macula | 20/320 | 69% |
| Outside the macula | 20/80 | 25% |
The main clinical findings are as follows.
When the tumor is in the macula, the prognosis is poor, and average vision is 20/320, much lower than with extramacular tumors (20/80). Over 4 years of follow-up, 60% of macular tumors lose 3 or more lines of vision, compared with 13% of extramacular tumors.
The cause of CHRRPE is unknown, and it is thought to be congenital, although no cases have been reported at birth. One proposed hypothesis is that undifferentiated ectopic precursor cells destined to become retinal pigment epithelium fail to complete differentiation and proliferate and accumulate within the neurosensory retina3).
Histologically, melanocytes, blood vessels, and glial cells are mixed in varying proportions2). Subtypes include a vascular-predominant type (reddish), a melanocyte-predominant type (blackish), and a glial-predominant type (whitish)2).
Regarding the mechanism of epiretinal membrane formation, glial cells and retinal pigment epithelial cells are thought to transdifferentiate into myofibroblast-like preretinal cells, altering the vitreoretinal interface and causing epiretinal membrane formation2).
It is usually congenital and nonhereditary, but it is sometimes associated with neurofibromatosis types 1 and 2.
Because the association with neurofibromatosis type 2 is strongest, screening for neurofibromatosis type 2 (brain MRI and genetic testing) should be considered, especially in cases with bilateral lesions or a family history of neurofibromatosis. Associations with neurofibromatosis type 1 and other systemic syndromes have also been reported, and systemic evaluation is recommended.
Multimodal imaging that combines multiple tests is important for diagnosing composite hamartoma of the retina and retinal pigment epithelium3).
Optical coherence tomography can show several findings that are specific to this disease.
Inner-layer predominant findings
Mini-peaks: A serrated appearance of the inner retina. It is characterized by the absence of outer-layer disruption. Useful for distinguishing it from idiopathic epiretinal membrane.
Shark-teeth sign: A triangular hyperreflective change in the outer nuclear layer. It can be seen even in mild cases of this disease7).
Full-thickness findings
Maxi-peaks: Retinal folds extending through the full thickness of the retina.
Omega sign: A wider and deeper variation of maxi-peaks. It is especially useful in distinguishing this disease in the macular area from idiopathic epiretinal membrane1)2).
Double retina sign: A new OCT finding in which the retina folds on itself. The defect is filled in by glial proliferation1).
As additional supportive tests, enhanced depth imaging OCT (EDI-OCT) has shown that the choroid beneath the tumor is on average 37% thinner than in the fellow eye7), and MP-1 microperimetry has shown that preoperative low-sensitivity areas indicate the attachment site of the epiretinal membrane and can be used as a predictor for surgery2).
A systematic classification based on three axes—location, features, and OCT findings—has been proposed and is used to determine management8)9).
The main differential diagnoses are listed below. The key distinguishing features from choroidal malignant melanoma are the presence of retinal feeder vessels and the deposition of large amounts of hard exudates.
Mini-peak (a saw-toothed appearance of the inner retina), maxi-peak/omega sign (a full-thickness retinal fold), and shark-teeth sign (triangular hyperreflective changes in the outer nuclear layer) are characteristic findings. These are also useful for distinguishing this disease from idiopathic epiretinal membrane.
Treatment for combined hamartoma of the retina and retinal pigment epithelium is individualized based on tumor location, stage, visual acuity, age, and symptoms. Stable cases are basically followed with regular multimodal imaging3).
Follow-up
Indications: Stable non-macular tumors, asymptomatic cases, and cases with good visual acuity.
Follow-up: Regular evaluation with multimodal imaging (optical coherence tomography, fluorescein fundus angiography, OCT angiography).
Amblyopia treatment: Extremely important because onset is in early childhood. Start early with measures such as patching the healthy eye.
Surgical intervention
Indications: progressive vision loss due to epiretinal membrane formation, tractional retinal detachment, and cases complicated by choroidal neovascularization.
Procedure: Vitrectomy with epiretinal membrane peeling (pars plana vitrectomy) is the main approach.
Pediatric cases: The combination of early surgery and postoperative amblyopia treatment is important.
In this disease when it begins in childhood, amblyopia often occurs, and early amblyopia treatment is directly linked to visual prognosis. Most cases that showed improved vision had received amblyopia treatment. A case has also been reported in which three weeks of full occlusion improved vision from 20/50 to 20/307).
Vitrectomy for this disease with epiretinal membrane has shown a certain degree of effectiveness in several studies.
| Report | Number of cases | Postoperative visual improvement rate |
|---|---|---|
| Aggregate of multiple studies2) | 43 cases (13 studies) | 90.7% (39/43) |
| Small-scale study2) | 15 cases | 93.3% (14/15) |
| Autologous plasmin enzyme-assisted method2) | 11 cases | 72.7% (8/11) |
During surgery, dyes are used to make the epiretinal membrane and internal limiting membrane easier to see. van der Sommen et al. (2021) reported a complete vitrectomy combined with triamcinolone for vitreous visualization and infracyanine green for internal limiting membrane staining, achieving a preoperative visual acuity of 1.3 LogMAR → postoperative 0.8 LogMAR and stability for 48 months5).
For tractional retinal detachment associated with this peripheral disease, if traction from the vitreous cortex membrane is the main cause, it is treated with vitreous traction membrane removal rather than epiretinal membrane removal. In some cases, retinal reattachment can be achieved without tamponade. In a report by Holekamp et al. (2021), vision improved from 20/40 to 20/16 at 18 months after surgery9).
In a review that pooled 13 small studies, postoperative visual improvement was achieved in 39 of 43 cases (90.7%)2). However, prognosis is poor when long-standing cystoid macular edema or membrane invasion into the tumor is present. In children, postoperative amblyopia treatment is essential for improving visual outcome.
The histologic features of combined hamartoma of the retina and retinal pigment epithelium are a disorganized glial component, proliferating strands and tubular structures of retinal pigment epithelium, and many blood vessels mixed together. Subtypes show different appearances depending on the predominant tissue component.
Two hypotheses have been proposed for how this disease develops1).
According to the hypothesis of LedesmaGil et al., tumor growth is thought to progress stepwise from the inner retina to the outer retina, and vascular structures are damaged as each layer becomes involved1).
The molecular mechanisms of epiretinal membrane formation are as follows2).
The choroid beneath the tumor in the affected eye has been confirmed to be, on average, 37% thinner than in the fellow eye7). This is thought to be due to replacement or compression of choroidal tissue by the tumor.
Naseripour et al. (2023) first reported a new OCT finding, double retina sign, in a case of this disease in a 7-year-old girl 1). This finding occurs when glial proliferation fills the retinal defect, and it was also seen together with omega sign. Visual acuity remained stable over 3 years of follow-up.
The shark-teeth sign (a triangular hyperreflective change in the outer nuclear layer) may help with early diagnosis of this disease, which is mild and easy to overlook 2)7).
van der Sommen et al. (2021) reported a surgical procedure that included complete removal of residual vitreous cortex using the vitreous wiping method in a case of this disease with a vasoproliferative tumor 5). Residual vitreous cortex has been pointed out as a possible scaffold for postoperative proliferative vitreoretinopathy, and the importance of complete removal is receiving attention.
Zhu et al. (2022) reported the clinical similarity between unilateral retinal pigment epitheliopathy (unilateral retinal pigment epitheliopathy, URPED) and this disease 6). It has been proposed that the juxtapapillary form of this disease and unilateral retinal pigment epitheliopathy may be part of the same disease spectrum (forme fruste), and further case accumulation will be needed for evaluation.
Standardizing the indications for epiretinal membrane surgery and the optimal timing of surgery, and building evidence through randomized controlled trials, are major future challenges 2). At present, only small retrospective studies are available, and there are limits to how accurately the treatment effect can be assessed.
